Thiamine deficiency induced pathologic damage in humans is associated with Wernicke-Korsakoff's disease, mixed sensory motor neuropathy, and infantile subacute necrotizing encephalopathy. The prevalence of Wernicke-Korsakoff pathologic changes ranges from 1.7-2.8% among all autopsies to as high as 12.5% among chronic alcoholics. Individuals with Wernicke-Korsakoff disease suffer from anterograde and retrograde amnesia, cognitive dysfunctions, multimodal sensory discrimination deficits, and emotional flattening and thus require constant care and institutionalization. An important feature of these thiamine deficiency disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary bodies, and certain brainstem nuclei are consistently damaged in Wernicke-Korsakoff s disease and are probably responsible for the behavioral deficits. Despite this knowledge, the biochemical and physiological mechanisms responsible for the lesions and their topographic distribution in the brain following acute thiamine deficiency remain unknown. Consequently, there is currently no therapeutic treatment for the abrupt cessation of ongoing pathologic events during acute thiamine deficiency. The long-term objective of this project is to develop effective treatments for the prevention of brain lesions and associated cognitive and memory deficits produced by thiamine deficiency. The immediate goal of this project is to test a recent hypothesis that suggests glutamate receptor-mediated neurotoxicity is involved in the brain lesions produced by acute thiamine deficiency. The specific goals are to conduct the following studies in the pyrithiamine induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's disease: i) measure by in vivo microdialysis the extracellular fluid levels of excitatory amino acids in affected and unaffected brain regions during acute thiamine deficiency; ii) quantitatively measure the effects of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, in reducing thiamine deficiency induced brain lesions; and iii) conduct an ultrastructural analysis of dendritic and somal degenerative changes induced by acute thiamine deficiency for evidence of 'excitotoxic' type of damage.